RT Journal Article
SR Electronic
T1 Metabolism of c-Met kinase inhibitors containing quinoline by aldehyde oxidase, electron donating and steric hindrance effect
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP dmd.118.081919
DO 10.1124/dmd.118.081919
A1 Jiang Wei Zhang
A1 Wen Xiao
A1 Zhen Ting Gao
A1 Zheng Tian Yu
A1 Ji Yue (Jeff) Zhang
YR 2018
UL http://dmd.aspetjournals.org/content/early/2018/09/12/dmd.118.081919.abstract
AB Some quinoline containing c-Met kinase inhibitors are aldehyde oxidase (AO) substrates. 3-substituted quinoline triazolopyridine analogues were synthesized to understand the electron donating and steric hindrance effect on AO-mediated metabolism. Metabolic stability studies for these quinoline analogues were carried out in liver cytosol from mice, rats, cyno monkeys, and humans. Several 3-N-substituted analogues were found to be unstable in monkey liver cytosolic incubations (t1/2 < 10 min), and five of them (63, 53, 51, 11, and 71) were chosen for additional mechanistic studies. Monooxygenation on the quinoline ring was identified by LC/MS/MS. Metabolite formation was inhibited by the AO inhibitors menadione and raloxifene, but not by the xanthine oxidase inhibitor allopurinol. It was found that small electron donating groups at the 3-quinoline moiety made the analogues more susceptible to AO metabolism, while large 3-substituents could reverse the trend. Although species differences were observed, this trend was applicable to all species tested. Small electron donating substituents at the 3-quinoline moiety increased both affinity (decreased Km) and Vmax towards AO in kinetic studies, while large substituents decreased both parameters probably due to steric hindrance. Based on our analysis, a common structural feature with high AO liability was proposed. Our finding could provide useful information for chemists to minimize potential AO liability when designing quinoline analogues.